The role of the innate immune system in granulomatous disorders

Abstract

The dynamic structure of the granuloma serves to protect the body from microbiological challenge. This organized aggregate of immune cells seeks to contain this challenge and protect against dissemination, giving host immune cells a chance to eradicate the threat. A number of systemic diseases are characterized by this specialized inflammatory process and granulomas have been shown to develop at multiple body sites and in various tissues. Central to this process is the macrophage and the arms of the innate immune response. This review seeks to explore how the innate immune response drives this inflammatory process in a contrast of diseases, particularly those with a component of immunodeficiency. By understanding the genes and inflammatory mechanisms behind this specialized immune response, will guide research in the development of novel therapeutics to combat granulomatous diseases.

Keywords: Crohn’s; autophagy; granuloma; innate; macrophage; neutrophil.

Figure 1

(A) Diagram of a mature granuloma. After 3 weeks of maturation, the granuloma is fully formed. Crosstalk between various cells of the immune system leads to proliferation of lymphocytes, predominantly T-helper cells. (a) Macrophages engulf the antigen and secrete pro-inflammatory cytokines. They also present antigen derived peptides and lipids via MHC class II and CD 1 molecules to T cells, natural killer T cells (NKT cells), and natural killer cells (NK cells). (b) Thl cells secrete IFNγ which activates dendritic cells. (c) Dendritic cells loaded with antigen migrate to the local lymph nodes where they present to naive CD4+ T cells. (d) Within the lymph node, the dendritic cells secrete IL-12 which stimulates these naive cells to differentiate into Thl cells. These in turn secrete IL2 to expand their population. (e) At the granuloma site, activated dendritic cells secrete copious amounts of TNFα which activates the endothelium, upregulating the number of adhesion molecules to allow extravasation of Thl cells and monocytes. (f) Thl cells secrete IFNγ which stimulates monocytes to differentiate into macrophages. (B) Diagrammatic representation of the multistep pathogenesis of Crohn’s disease. (1) Loss of integrity in the gut epithelium allows bacteria to leave the lumen and enter the tissue of the gut. (2) Defective autophagy. (3) Mutation of NOD2 leads to reduction in secretion of pro-inflammatory cytokines including TNFα. (4) Defect in Neutrophil function (monogenic diseases) or reduced chemotaxis (inherited or due to reduced TNFα secretion). This leads to persistence of bacterium in the tissues. (5) Mutational the IL23R on Thl7 cells leads to increased survival of these cells and increased IL17 production. High levels of IL17 is associated with increased bowel inflammation in Crohn’s. (6) Mutation of ATG16L (T300A) leads to a excessive of production of IL-lβ. (7) Mutation in NOD2 leads to reduced defensin production by intestinal Paneth cells.

Figure 1

(A) Diagram of a mature granuloma. After 3 weeks of maturation, the granuloma is fully formed. Crosstalk between various cells of the immune system leads to proliferation of lymphocytes, predominantly T-helper cells. (a) Macrophages engulf the antigen and secrete pro-inflammatory cytokines. They also present antigen derived peptides and lipids via MHC class II and CD 1 molecules to T cells, natural killer T cells (NKT cells), and natural killer cells (NK cells). (b) Thl cells secrete IFNγ which activates dendritic cells. (c) Dendritic cells loaded with antigen migrate to the local lymph nodes where they present to naive CD4+ T cells. (d) Within the lymph node, the dendritic cells secrete IL-12 which stimulates these naive cells to differentiate into Thl cells. These in turn secrete IL2 to expand their population. (e) At the granuloma site, activated dendritic cells secrete copious amounts of TNFα which activates the endothelium, upregulating the number of adhesion molecules to allow extravasation of Thl cells and monocytes. (f) Thl cells secrete IFNγ which stimulates monocytes to differentiate into macrophages. (B) Diagrammatic representation of the multistep pathogenesis of Crohn’s disease. (1) Loss of integrity in the gut epithelium allows bacteria to leave the lumen and enter the tissue of the gut. (2) Defective autophagy. (3) Mutation of NOD2 leads to reduction in secretion of pro-inflammatory cytokines including TNFα. (4) Defect in Neutrophil function (monogenic diseases) or reduced chemotaxis (inherited or due to reduced TNFα secretion). This leads to persistence of bacterium in the tissues. (5) Mutational the IL23R on Thl7 cells leads to increased survival of these cells and increased IL17 production. High levels of IL17 is associated with increased bowel inflammation in Crohn’s. (6) Mutation of ATG16L (T300A) leads to a excessive of production of IL-lβ. (7) Mutation in NOD2 leads to reduced defensin production by intestinal Paneth cells.